Compositions for topical use having melanin synthesis-inhibiting activity

ABSTRACT

Compositions for topical use having melanin synthesis-inhibiting activity comprising kojic acid or its esters and vitamin C or its derivatives. The compositions have excellent human skin-whitening effect and anti-suntan effect.

BACKGROUND OF THE INVENTION

The present invention relates to compositions for external use having a melanin synthesis-inhibiting activity, which can be formulated in cosmetic compositions or ointments to exhibit a human skin-whitening effect and anti-suntan effect.

It is known that kojic acid and its ester have an effect to inhibit synthesis of melanin (Japanese Tokkyo Kokai No. 18739/1978, No. 7776/1981, No. 79616/1981, No. 33207/1984).

Kojic acid or its esters have an action to inhibit an activity of tyrosinase which is the enzyme to convert tyrosine to dopa, then to dopa quinone in the pathway of melanin synthesis, whereby the synthesis of melanin is prevented.

The present inventor has intensively studied the kojic acid or its esters, in order to obtain more effective melanin synthesis-inhibiting activity, by producing various derivatives of kojic acid or its esters or by using with other drugs. As a result of the study, it has been found a surprising fact that the melanin synthesis can be synergistically inhibited by blending vitamin C or its derivatives with kojic acid or its esters, and then the present invention has been completed.

SUMMARY OF THE INVENTION

According to the present invention there can be provided compositions for topical use having the melanin synthesis-inhibiting activity comprising an effective amount of kojic acid or its esters and vitamin C or its derivatives.

DETAILED DESCRIPTION

As mentioned above it has been known that the kojic acid and its esters have the melanin synthesis-inhibiting activity, and also that a large dose of vitamin C can exhibit a whitening effect of human skin. When the two compounds are blended, however, the blended agent can give a surprising effect which is not an additive effect by a synergistic effect, i.e. as explained hereinafter the excellent effect can be obtained by blending a small amount of vitamin C. Though the mechanism of this synergistic effect has not yet been clear, it is seemed that a certain delicate correlation occurs in addition to a complementary effect in which a part of effect which cannot be covered with one compound is covered with the other compound.

The kojic acid or its esters which is one of the active ingredients of the present invention is preferably represented by the formula: ##STR1## wherein R¹ and R² are the same or different, and each is hydrogen atom or an acyl group of 3 to 20 carbon atoms.

Non-exclusive examples of the esters are, for instance, kojic acid monoesters such as kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, kojic acid monostearate, kojic acid monocinnamoate and kojic acid monobenzoate; kojic acid diesters such as kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate and kojic acid dioleate. Preferred monoester is an ester in which a OH group at 5-position of kojic acid is esterified. Esterification can improve stabilities against pH or sun light, while maintaining a melanin synthesis-inhibiting activity equal to that of kojic acid.

Another active ingredient is vitamin C or its derivatives. Non-exclusive examples of the derivatives are, for instance, alkyl esters of L-ascorbic acid such as L-ascorbyl palmitate, L-ascorbyl isopalmitate, L-ascorbyl dipalmitate, L-ascorbyl diisopalmitate, L-ascorbyl stearate, L-ascorbyl isostearate, L-ascorbyl distearate, L-ascorbyl diisostearate, L-ascorbyl myristate, L-ascorbyl isomyristate, L-ascorbyl dimyristate, L-ascorbyl diisomyristate, L-ascorbyl 2-ethylhexanoate, L-ascorbyl di-2-ethylhexanoate, L-ascorbyl oleate and L-ascorbyl dioleate; phosphates of L-ascorbic acid such as L-ascorbyl-2-phosphate and L-ascorbyl-3-phosphate; sulfates of L-ascorbic acid such as L-ascorbyl-2-sulfate and L-ascorbyl-3-sulfate; their salts with alkali metals such as sodium and pottasium; and their salts with alkaline earth metals such as calcium and magnesium. They can be used alone or in a mixture of two or more.

The comoposition for topical use of the present invention comprises the kojic acid or its ester and the vitamin C or its derivative, and may be prepared in various forms which can exhibit the melanin synthesis-inhibiting activity and whitening effect and anti-suntan effect, e.g. in a form of cosmetic preparation such as cream, cosmetic lotion, pack or powder, or in a form of quasidrug such as emulsion, lotion, liniment or ointment. In each formulation, there may be used usual additives such as base material, excipient, stabilizer, pigment, fragrance, UV-absorbent, antioxidant, antiseptics, metal deactivator and organic acid.

Mixing ratio of kojic acid or its esters to vitamin C or its derivatives varies with their kind or combination, and is generally 1:0.01 to 1:20 by weight, preferably 1:0.1 to 1:10. Total amount of the active ingredients varies with manner of use, object of use, method of use and preparation form, and is, for example, in cosmetics 0.01 to 20% (% by weight, hereafter the same), preferably 0.5 to 10%, and in ointments 0.01 to 10%, preferably 0.5 to 5%.

The active ingredients of the present invention, i.e. kojic acid, its esters, vitamin C and its derivatives are non toxic to human, and also mixture thereof can be used without any trouble.

The present invention is more specifically described and explained by means of the following Examples. It is to be understood that the present invention is not limited to those Examples, and may be made various changes and modifications without departing from the scope or spirit of the present invention.

EXAMPLE 1

B-16 Cultured cells derived from mouse melanoma cells were inoculated in Eagle's minimum essential medium containing 10% fetal bovine serum to which kojic acid and vitamin C or its derivative are added in an amount shown in Table 1. The B-16 cells were cultured for 5 days at 37° C. under 5% CO₂ atmosphere, then dispersed with trypsin, and then centrifuged at 1,000 rpm for 5 minutes to collect the cells. Darkness of the cell pellet was observed with naked eyes, and evaluated according to the following standard.

-: Same color as that when a melanin synthesis-inhibiting agent is not added.

+: Slightly whitened.

++: Considerably whitened.

+++: Almost whitened.

The results are shown in Table 1.

                  TABLE 1                                                          ______________________________________                                         Vitamin C or its derivative                                                                     Concentration of                                                       Concentration                                                                              Kojic acid   Depigmenting                                 Kind     (mM)        (mM)         Effect                                       ______________________________________                                         --       --          0.5          ±                                         --       --          1.0          +                                            Vitamin C                                                                               0.2         --           -                                                     0.4         --           -                                                     0.2         0.5          +                                                     0.4         0.5          ++                                           Magnesium                                                                               0.5         --           -                                            salt of  1.0         --           -                                            L-ascorbyl-                                                                             0.5         0.5          +                                            2-phosphate                                                                             1.0         0.5          ++                                           Sodium   0.5         --           -                                            salt of  1.0         --           -                                            L-ascorbyl-                                                                             0.5         0.5          +                                            2-sulfate                                                                               1.0         0.5          ++                                           ______________________________________                                    

EXAMPLE 2

On the inner side of right upper arm of each volunteer (thirty healthy men and women), a test site (2 cm×2 cm) was provided. Before irradiation with ultraviolet rays the test site was carefully washed with warm water and was wrapped around the test site with aluminum foil so that only the test site was irradiated with ultraviolet rays. The irradiation was carried out three consecutive days at a dose of 0.8×10⁷ erg/cm³ per each irradiation per one day with four lamps (FL20S.BLB Lamp×2 and FL20S.E-30 Lamp×2 available from Toshiba Co., Ltd.) which were set at a distance of 10 cm from the test site. After the irradiation, the following test composition (vanishing cream) was applied everyday to the irradiated site three times per day (morning, noon, night). After three weeks, degree of pigmentation of the test site was observed with naked eyes. The improvement of the pigmentation was evaluated by the number of volunteers in three degrees, i.e. very effective, effective or non-effective. The results are shown in Table 2.

    ______________________________________                                         (Test composition)    Part by weight                                           ______________________________________                                         (A)  Kojic acid ester shown in Table 2                                                                   1.00                                                      Polyoxyethylene (40) monostearate                                                                   2.00                                                      Glycerol monostearate                                                                               5.00                                                      (selfemulsifying type)                                                         Stearic acid         5.00                                                      Behenyl alcohol      1.00                                                      Liquid paraffin      1.00                                                      Glyceryl trioctanoate                                                                               10.00                                                     Antiseptics          proper                                                    Fragrance            slight                                               (B)  Vitamn C or its derivative                                                                          1.00                                                      shown in Table 2                                                               1,3-Butylene glycol  5.00                                                      Purified water       remain                                               ______________________________________                                    

PREPARATION

The ingredients (A) are melted by heating to obtain an oil phase. Separately the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give a vanishing cream.

                                      TABLE 2                                      __________________________________________________________________________                               Number of the volunteers                             Kojic acid ester                                                                           Vitamin C and its derivative                                                                 Very effective                                                                         Effective                                                                           Non-effective                           __________________________________________________________________________     --          Vitamin C     0       8    22                                      --          L-Ascorbyl dipalmitate                                                                       0       7    23                                      --          L-Ascorbyl stearate                                                                          0       8    22                                      --          L-Ascorbyl-2-phosphate                                                                       0       10   20                                      --          L-Ascorbyl-2-sulfate                                                                         0       8    22                                      Kojic acid monostearate                                                                    --            3       6    21                                      "           Vitamin C     5       11   14                                      "           L-Ascorbyl dipalmitate                                                                       4       10   16                                      "           L-Ascorbyl stearate                                                                          5       11   14                                      "           L-Ascorbyl-2-phosphate                                                                       6       12   12                                      "           L-Ascorbyl-2-sulfate                                                                         5       10   15                                      Kojic acid dipalmitate                                                                     --            2       8    20                                      "           Vitamin C     4       12   14                                      "           L-Ascorbyl dipalmitate                                                                       5       11   14                                      "           L-Ascorbyl stearate                                                                          4       10   16                                      "           L-Ascorbyl-2-phosphate                                                                       5       13   12                                      "           L-Ascorbyl-2-sulfate                                                                         5       13   12                                      __________________________________________________________________________

The followings are typical formulations of the melanin synthesis-inhibiting agent of the present invention. It is to be understood that the present invention is not limited to the formulations.

    ______________________________________                                         Lotion               Part by weight                                            ______________________________________                                         Polyoxyethylene (60) hydrogenated                                                                   1.00                                                      castor oil                                                                     Ethanol              15.00                                                     Citric acid          0.10                                                      Sodium citrate       0.30                                                      1,3-Butylene glycol  4.00                                                      Kojic acid           1.00                                                      Sodium salt of       2.00                                                      L-ascorbyl-2-phosphate                                                         Antiseptics          proper                                                    Fragrance            slight                                                    Purified water       remain                                                    ______________________________________                                    

PREPARATION

The all ingredients are homogeneously mixed and dissolved with stirring to give a lotion.

    ______________________________________                                         Emulsion              Part by weight                                           ______________________________________                                         (A)    Polyoxyethylene (20) behenyl                                                                      0.50                                                        ether                                                                          Polyoxyethylene (60) sorbitol                                                                     1.00                                                        tetraoleate                                                                    Glyceryl monostearate                                                                             1.00                                                        (hydrophilic type)                                                             Stearic acid       0.50                                                        Behenyl alcohol    0.50                                                        Avocado oil        1.00                                                        Natural vitamin E  0.02                                                        Kojic acid monopalmitate                                                                          2.00                                                        Antiseptics        proper                                                      Fragrance          slight                                               (B)    1,3-Butylene glycol                                                                               5.00                                                        Carboxyvinyl polymer                                                                              0.10                                                        Sodium N-lauroyl-L-glutamate                                                                      0.50                                                        Magnesium salt of  1.00                                                        L-ascorbyl-2-phosphate                                                         Purified water     remain                                               ______________________________________                                    

PREPARATION

The ingredients (A) are melted by heating to obtain an oil phase. Separately the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give an emulsion.

    ______________________________________                                         Jellied pack     Part of weight                                                ______________________________________                                         Citric acid      0.20                                                          Propylene glycol 4.00                                                          Glycerin         4.00                                                          Ethanol          2.00                                                          Carboxyvinyl polymer                                                                            1.00                                                          Pottasium carbonate                                                                             0.60                                                          Kojic acid       0.50                                                          Magnesium salt of                                                                               0.50                                                          L-ascorbyl-2-sulfate                                                           Antiseptics      proper                                                        Fragrance        slight                                                        Purified water   remain                                                        ______________________________________                                    

PREPARATION

The all components are homogeneously mixed and dissolved with stirring to give a jellied pack.

    ______________________________________                                         Creamy pack            Part by weight                                          ______________________________________                                         (A)    Poyoxyethylene (20) behenyl                                                                        1.00                                                       ether                                                                          Polyoxyethylene (40) sorbitol                                                                      2.00                                                       tetraoleate                                                                    Glycerin monostearate                                                                              2.00                                                       (hydrophilic type)                                                             Behenyl alcohol     3.00                                                       Squalane            25.00                                                      Glycerine octanoate 10.00                                                      Natural vitamin E   0.04                                                       Kojic acid monocinnamoate                                                                          2.00                                                       L-Ascorbyl dipalmitate                                                                             0.50                                                       Antiseptics         proper                                                     Fragrance           slight                                              (B)    1,3-Butylene glycol 5.00                                                       Sodium dl-pyrrolidonecarboxylate                                                                   1.50                                                       Citric acid         0.04                                                       L-Ascorbyl-2-phosphate                                                                             0.50                                                       Purifed water       remain                                              ______________________________________                                    

PREPARATION

The ingredients (A) are melted by heating to obtain an oil phase. Separately, the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give a creamy pack.

    ______________________________________                                         Ointment              Part by weight                                           ______________________________________                                         (A)    Polyoxyethylene (60) sorbitan                                                                     1.00                                                        monostearate                                                                   Polyoxyethylene (60) sorbitol                                                                     1.50                                                        tetraoleate                                                                    Glycerin monostearate                                                                             1.50                                                        (selfemulsifying type)                                                         Beeswax            2.00                                                        Paraffin           2.00                                                        Stearic acid       3.00                                                        Behenyl alcohol    3.00                                                        Shea butter        12.00                                                       Liquid paraffin    5.00                                                        Natural vitamin E  0.04                                                        Methyl polysiloxane                                                                               0.01                                                        Kojic acid monobenzoate                                                                           3.00                                                        Antiseptics        proper                                                      Fragrance          slight                                               (B)    1,3-Butylene glycol                                                                               5.00                                                        Citric acid        0.30                                                        Sodium dl-lauroyl-L-glutamate                                                                     0.50                                                        Pottasium salt of L-ascorbyl-                                                                     1.00                                                        2-phosphate                                                                    Purified water     remain                                               ______________________________________                                    

PREPARATION

The ingredients (A) are melted by heating to obtain an oil phase. Separately, the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give an ointment.

    ______________________________________                                         Whitening powder Part by weight                                                ______________________________________                                         Octyldodecyl myristate                                                                          1.0                                                           Kojic acid       2.0                                                           L-Ascorbyl stearate                                                                             5.0                                                           Fragrance        slight                                                        Maltitol         remain                                                        ______________________________________                                    

PREPARATION

The all ingredients are homogeneously mixed to give a whitening powder. 

What is claimed is:
 1. A composition for topical use which has a melanin synthesis-inhibiting activity, comprising kojic acid or an ester of kojic acid and vitamin C or or a derivative of vitamin C.
 2. The composition of claim 1, wherein the kojic acid or ester of kojic acid is a compound of the formula ##STR2## wherein R¹ and R² are the same or different, and each is hydrogen or an acyl group of 3 to 20 carbon atoms.
 3. The composition of claim 2, wherein the kojic acid ester is a member selected from the group consisting of kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, kojic acid monostearate, kojic acid monocinnamoate, kojic acid monobenzoate, kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate, kojic acid dioleate and a mixture thereof.
 4. The composition of claim 1, wherein the derivative of vitamin C is a member selected from the group consisting of an alkyl ester of L-ascorbic acid, a phosphate of L-ascorbic acid, a sulfate of L-ascorbic acid, a metal salt thereof and a mixture thereof.
 5. A composition for topical use which has a melanin synthesis-inhibiting activity, comprising 1 part by weight of kojic or an ester of kojic acid and 0.01 to 20 parts by weight of vitamin C or a derivative of vitamin C. 